Organic contrast agent analog and method of making same

ABSTRACT

An organic contrast agent analog is derived to contain fluorine moieties. A method for making the organic contrast agent analog includes the steps of fluorinating the contrast agent analog for increasing the acidity of the analog to increase the choleretic activity of the analog and to render it less toxic.

TECHNICAL FIELD

The present invention relates to organic contrast agent analogs and methods of making the analogs. More particularly, the present invention relates to a method of decreasing the toxicity of such agents through chemical modification.

BACKGROUND ART

In general, current cholangiographic agents used as biliary X-ray contrast agents are now considered too toxic to meet risk/benefit criteria for routine use as contrast agents to visualize the biliary system. Because of the relative toxicity of these agents, these agents are being replaced in use by alternative imaging methodologies, such as ultrasound and magnetic resonance imaging (MRI). On the other hand, the resolution achievable with X-ray radiology techniques is superb. Accordingly, biliary contrast agents can still be quite useful.

A second issue with regard to these agents is the low rate of choleresis associated with biliary excretion of the agent. The low rate of choleresis increases the biliary concentration and thus increases the toxicity.

Current biliary X-ray contrast agents have amphophilic properties. These agents have a hydrophilic head portion; that is, the --CO₂ H terminus, and a hydrophobic tail; that is, triiodo aniline moiety with an unsubstituted 5-position. Because of this property, they are excreted nearly exclusively by the biliary route. Typical of most amphilphilic molecules, these biliary contrast agents tend to self associate. This property is reflected by the low critical micellar concentration and low osmolalities of their aqueous salt solution.

It is therefore desirable to produce a less toxic and more choleretic contrast agent.

SUMMARY OF THE INVENTION

In accordance with the present invention, there is provided an organic contrast agent analog wherein the analog is an oral or intravenous media having the formula I: ##STR1## and R₁ and R₂ are

    ______________________________________                                         R.sub.1              R.sub.2                                                   ______________________________________                                         Iopa- noic acid                                                                       ##STR2##          NH.sub.2                                              Ipoda- tic acid                                                                      CH.sub.2 CH.sub.2 COOH                                                                            NCHN(CH.sub.3).sub.2                                  Tyro- panoic acid                                                                     ##STR3##          NHCOCH.sub.2 CH.sub.2 CH.sub.3                        Ioce- tamic acid                                                                      ##STR4##          NH.sub.2                                              Iopro- nic acid                                                                       ##STR5##          NHCOCH.sub.3                                          Isou- metic acid                                                                      ##STR6##          NHCH.sub.3                                            ______________________________________                                    

wherein the analog includes one or more flourine substitutions or additions.

The present invention further provides a method of making the organic contrast agent analog including the steps of forming the organic contrast agent analog having formulas I, II, or III and substituting or adding at least one flourine moiety to the analog.

FIGURES IN THE DRAWINGS

Other advantages of the present invention will be readily appreciated as the same becomes better understood by reference to the following detailed description when considered in connection with the accompanying drawings wherein:

FIGS. 1 and 2 are high resolution NMR proton spectrums;

FIG. 3 is a high resolution NMR fluorine spectrum;

FIGS. 4 and 5 are mass spectrum analyses performed on TFA-IOP made in accordance with the present invention;

FIG. 6 is a plotted curve comparing biliary concentration over time of IOP versus TFA-IOP;

FIG. 7 is comparitive data of TFA-IOP and IOP plasma concentration versus time; and

FIG. 8 is comparative date of TFA-IOP and IOP biliary excretion concentration versus time.

DESCRIPTION OF THE INVENTION

Generally, an organic contrast agent analog made in accordance with the present invention has the following general formula I: ##STR7## and R₁ and R₂ are

    ______________________________________                                         R.sub.1              R.sub.2                                                   ______________________________________                                         Iopa- noic acid                                                                       ##STR8##          NH.sub.2                                              Ipoda- tic acid                                                                      CH.sub.2 CH.sub.2 COOH                                                                            NCHN(CH.sub.3).sub.2                                  Tyro- panoic acid                                                                     ##STR9##          NHCOCH.sub.2 CH.sub.2 CH.sub.3                        Ioce- tamic acid                                                                      ##STR10##         NH.sub.2                                              Iopro- nic acid                                                                       ##STR11##         NHCOCH.sub.3                                          Isou- metic acid                                                                      ##STR12##         NHCH.sub.3                                            ______________________________________                                    

or wherein said analog is an intravenous media having the formula II; ##STR13## and R₃ is

    ______________________________________                                                   R.sub.3                                                              ______________________________________                                         Iodipamide  NHCO(CH.sub.2).sub.4 CONH                                          Ioglycamide NHCOCH.sub.2OCH.sub.2 CONH                                         Iodoxamate  NHCO(CH.sub.2 CH.sub.2 O).sub.4 CH.sub.2 CH.sub.2 CONH             Iotroxamide NHCO(CH.sub.2 OCH.sub.2).sub.3 CONH                                Iosulamide* NHCOCH.sub.2 CH.sub.2 SO.sub.2 CH.sub.2 CH.sub.2 CONH              ______________________________________                                          ##STR14##                                                                     ?  or wherein said analog is an urographic media having the formula III;        ##STR15##

The agent includes a hydrophilic head (side chain) and a hydrophilic tail (benzine ring). The flourine addition or substitution provides means for increasing the acidity of the agent and increasing the choleretic activity of the agent to render the agent less toxic.

Examples of oral cholecystographic contrast media which can be modified in accordance with the present invention are

                                      TABLE 1                                      __________________________________________________________________________                proprietary      Molecular weight (m.w.)                                                                     Iodine                                Common name                                                                               name      Manufacturer                                                                          Acid form                                                                             Salt form                                                                            (%/m.w.)                              __________________________________________________________________________     Iopanoic acid                                                                             Telepaque Winthrop                                                                              571          66.7                                  Ipodate, calcium                                                                          Oragratin, calcium                                                                       Squibb 598    1.234 63.7                                  Ipodate, sodium                                                                           Oragratin, sodium                                                                        Squibb 598    620   63.7                                  Tyropanoate, sodium                                                                       Bilopaque Winthrop                                                                              641    663   59.4                                  Iocetamic acid                                                                            Cholebrine                                                                               Mallinckrodt                                                                          614          62.0                                  Iopronic acid                                                                             Oravue    Squibb 673          56.6                                  Iosumetic acid       Schering                                                                              628          60.6                                  __________________________________________________________________________

Examples of intravenous cholangiographic media modifiable in accordance with the present invention are

                                      TABLE 2                                      __________________________________________________________________________     V-Methylglucamine salt                                                                     Proprietary   Molecular weight (m.w.)                                                                     Iodine                                  of contrast media                                                                          name   Manufacturer                                                                          Acid form                                                                             Salt form                                                                            (%/m.w.)                                __________________________________________________________________________     Iodipamide  Chologratin                                                                           Squibb 1.140  1.530 66.8                                    Ioglycamide Biligram                                                                              Schering                                                                              1.128  1.518 67.5                                    Iodoxamate  Cholevue                                                                              Winthrop                                                                              1.288  1.678 59.1                                    Iotroxamide        Schering                                                                              1.316  1.706 57.9                                    Iosulamide         Winthrop                                                                              1.376  1.764 55.3                                    __________________________________________________________________________

More specifically, the starting agent can be a cholangiographic or cholecystographic agent as stated above. The agent can be of the oral or intravenous types. That is, the agent is iodinated such that it can be used as a biliary X-ray contrast agent for routine use to visualize hepatocytes gallbalder and the the biliary system. Unlike previously used cholecystographic agents, such as underivatized iopanoic acid, the present invention is a chemically modified organic contrast agent analog which is rendered less toxic and more choleretic by the modification of the agent including additional fluorine functionalities on the agent, the fluorine functionalities rendering the agent more acidic and more choleretic.

It has been hypothesized that if an amphophilic molecule, such as a common organic contrast agent analog is rendered a stronger acid and is fully or at least more disassociated at physiological pH, it will most likely be excreted unconjugated, without causing choloresis and without being trapped in the intrahepatic shunt pathway (Sawkat, MS. et al; Influence of sid-chain charge on hepatic transport of bile acids and bile acid analogues. American Journal Physiology 249:G479-G488, 1985; Gurantz D., et al; Influence of bile acid structure on bile flow and biliary lipid secretion in the hamster. American Journal Physiology 247:G738G748, 1984; Yoon YB, et al, Effect of side-chain shortening on the physiologic properties of bile acids: hepatic transport and effect on biliary sectetion of 23-nor-ursodeoxycholate in rodents. Gastroenterology 90:837-852, 1986). Even in the presence of choleresis, if the hepatocyte and canalicular transport steps are rapid, the biliary contrast agent is expected to move as a bolus, and anatomical details, such as the intrahepatic ducts, can be visualized in patients with good hepatocyte function.

For example, the agent can be N-trifluoroacetyl-iopanoic acid or alpha-fluoro-N-trifluoroacidic-iopanoic acid.

The present invention further provides a method of making the organic contrast agent analog. The method generally includes the steps of forming the organic contrast agent analog having the formulas I, II, or III and then increasing the acidity of the agent while increasing the choleretic activity of agent to render the agent less toxic by adding or subtituting flourine on the agent.

EXPERIMENTS 1. Synthesis of N-trifluoro Derivative of Iopanoic Acid

Three fluorine atoms were attached to the cholecystographic agent iopanoic acid (IOP) so that it could be detected using 19-F magnetic resonance techniques.

IOP was reacted with trifluoroacetic anhydride at 0° C. in tetrahydrofuran. After the reaction was complete, the organic solvents were removed. The residue was dissolved in ethyl acetate and washed twice with water. The organic layer was dried over magnesium sulphate and the solvent was removed to obtain the final product. The product, N-trifluoroacetyl iopanoic acid, had a melting point of 193° C. and an extension coefficient of approximately 37,000 at 232 nm. The assigned structure was verified using high resolution proton and fluorine NMR spectroscopy, elemental analysis and mass spectrum analysis The isolated yield of the product was 97.5%.

The following summarizes the reaction. ##STR16##

2. Synthesis of Alpha-fluoro-N-trifluoroacetyl-Iopanoic Acid

Functional groups were placed on the carbon atom alpha to the carboxyl group of the organic contrast agent, iopanoic acid. A fluorine atom was placed on the carbon atom alpha to the carboxyl group of N-trifluoroacetyl-iopanoic acid to significantly effect its pKa and thus, effect its biodistribution and metabolism. The following summarizes the synthesis of the alpha-fluoro-N-trifluoroacetyliopanoic acid. ##STR17##

Results of elemental analysis of TFA-IOP provided by Galbraith Laboratories, Inc., Knoxville, Tenn. are as follows:

    ______________________________________                                         Galbraith        Theoretical                                                                              Error                                               ______________________________________                                         C      24.33%        24.03%    +0.30%                                          H      1.93%         2.15%     -0.22%                                          N      2.04%         2.00%     +0.04%                                          F      8.50%         8.15%     -0.35%                                          I      55.24%        54.51%    +0.73%                                          O                    9.16%                                                                          100.00%                                                   ______________________________________                                    

The calculations are based on the inclusion of a molecule of methanol with each molecule of TFA-IOP.

High resolution NMR proton spectrums (FIGS. 1 and 2), high-resolution NMR fluorine spectrum (FIG. 3) and mass spectrum analyses (FIGS. 4 and 5) were performed on TFA-IOP. The results of each confirm the expected chemical structure of the new compound. Mass spectral analysis was performed.

3. Comparative Data of Biliary Excretion of IOP and Trifluoroacetyl IOP

Experiments were conducted to compare the biodistribution and excretion of TFA-IOP to that of the parent compound IOP. TFA-IOP and IOP were each administered intravenously to rats (100 umol/kg) in order to compare the biodistribution and excretion of the compound made in accordance with the present invention and the parent compound. Tissues examined included liver, spleen, upper GI, lower GI, kidney, lung and heart. The length of each study was 90 minutes, during which time bile, urine and plasam samples were taken to monitor uptake and excretion. NMR relaxation rates for liver and plasma were also examined to note whether uptake of either compound might possible alter these parameters.

4. Results

In general, liver concentrations 90 minutes post injection were 512 uM and 202 uM after IOP and TFA-IOP injection, respectively, while kidney concentrations were 105 uM and 5 uM. Lesser concentrations were found in the other tissues. Excretion of the two compounds were found only in bile with no compound detected in urine. In bile, TFA-IOP reached a maximum concentration of 0.5 uM with the recovery of 40% of the injection dose during a 90 minute time period (see FIG. 6). For IOP, the biliary concentration reached 10 mM with 18% of the injected does recovered during the 90 minute collection period as shown in FIG. 6. Plasma disappearance curves were similar in form, as shown in FIG. 7. Thin layer chromatography of bile indicated that a vast majority of the injected TFA-IOP was metabolized to a single metabolite. No nonmetabolized compound was found

These results indicate that TFA and IOP are similar to their biodisposition except the rate of biliary excretion of TFA-IOP appears to be approximately twice that of IOP, as shown in FIG. 8.

Tables 1 through 5 summarizes the results of each experiment conducted. Table 6 shows a more detailed analysis of the tissue concentration results with values such as total micromoles in tissue, percent of dose/gm, etc.

Tables 7 and 8 contain analysis of the bile excretion results.

                  TABLE 1                                                          ______________________________________                                         TISSUES:                                                                               -IOP CONCENTRATION (uM)                                                        90 MIN POST INJECTION                                                          I-6     % OF     I-8        % OF                                               (IOP)   DOSE     (TFA-IOP)  DOSE                                       ______________________________________                                         LIVER     511.90    14.53    201.73   6.04                                     KIDNEY    105.40    0.69      57.84   0.34                                     *UPPER GI 307.81    1.31     140.23   0.41                                     *LOWER GI 135.23    0.59     178.09   0.63                                     *SPLEEN   255.54    0.45     164.06   0.24                                     *LUNG     324.91    1.21     277.64   0.83                                     *HEART    259.38    0.72     242.85   0.72                                     ______________________________________                                          No standard curves were compiled for these tissues. The values given           represent concentrations generated using the LIVER analysis routine and        standard curve. Because this routine utilizes a control LIVER spectra for      background modeling, erroneous Iodine concentration values for these           tissues may result due to inappropriate background removal.              

                  TABLE 2                                                          ______________________________________                                         PLASMA:                                                                                   -IOP CONCENTRATION (uM)                                             SAMPLING     I-6         I-8                                                   TIME (min)   (IOP)       (TFA-IOP)                                             ______________________________________                                          0           ****         0.00                                                 10           ****        863.19                                                20           ****        603.93                                                30           556.68      573.38                                                40           ****        510.22                                                50           507.76      469.19                                                60           462.07      414.69                                                70           462.46      373.79                                                80           403.95      403.05                                                90           372.89      359.94                                                ______________________________________                                          ****Indicates that no samples were obtained for these time periods.      

                  TABLE 3                                                          ______________________________________                                         BILE:                                                                                     -IOP CONCENTRATION (uM)                                             SAMPLING     I-6         I-8                                                   TIME (min)   (IOP)       (TFA-IOP)                                             ______________________________________                                          0           ****         635.0                                                 5           1605.8      3010.0                                                15           8659.4      5777.6                                                25           10504.9     6436.1                                                35           9854.3      7802.9                                                45           9667.6      7641.1                                                55           7316.4      8461.4                                                65           7529.1      5372.5                                                75           7758.8      5305.7                                                85           9564.6      4663.1                                                ______________________________________                                          ****Indicates that no sample was obtained for this time period.          

                  TABLE 4                                                          ______________________________________                                         URINE:                                                                                    -IOP CONCENTRATION (uM)                                             SAMPLING     I-6         I-8                                                   TIME (min)   (IOP)       (TFA-IOP)                                             ______________________________________                                          0-20        0           0                                                     20-40        0           0                                                     40-60        0           ***                                                   60-80        0           ***                                                   80-90        0           ***                                                   ______________________________________                                          ***Indicates that no samples were obtained for these time periods.       

                  TABLE 5                                                          ______________________________________                                         NMR DATA:                                                                               CONTROL        I-6     I-8                                            TISSUE   VALUE          (IOP)   (TFA-IOP)                                      ______________________________________                                                T1 VALUES (msec)                                                        Liver    214.96         228.26  243.07                                         Plasma   1332.65        1406.19 1455.34                                               T2 VALUES (msec)                                                        Liver     38.27          28.65   28.94                                         Plasma   232.18         257.87  221.56                                         ______________________________________                                          As expected, the values obtained do not significantly differ from control      values                                                                   

                                      TABLE 6                                      __________________________________________________________________________                                uMOLES      PERCENTAGE OF DOSE                             TISSUE                                                                               % OF               PER         PER                                       WEIGHT                                                                               B.WT.         IN TISS.                                                                            gram                                                                              kg  IN TISS.                                                                            gram                                                                              kg b.wt                         __________________________________________________________________________     INTRAVENOUS IOP RAT STUDY                                                      RAT NUMBER:                                                                               6.                                                                  DOSE:     104.umoles/kg                                                        TIME:      90.minutes                                                          BODY WEIGHT:                                                                             406.grams                                                            LIVER  11.98 2.95          6.13 .51                                                                               511.90                                                                             14.52                                                                               1.21                                                                              35.77                           SPLEEN  .75  .18           .19  .26                                                                               255.54                                                                             .45  .61                                                                               1.12                            UPPER GI                                                                              1.79  .44           .55  .31                                                                               307.91                                                                             1.31 .73                                                                               3.22                            LOWER GI                                                                              1.83  .45           .25  .14                                                                               135.23                                                                             .59  .32                                                                               1.44                            KIDNEY 2.76  .68           .29  .11                                                                               105.40                                                                             .69  .25                                                                               1.70                            LUNG   1.57  .39           .51  .32                                                                               324.91                                                                             1.21 .77                                                                               2.98                            HEART  1.18  .29           .31  .26                                                                               259.38                                                                             .72  .61                                                                               1.79                            __________________________________________________________________________     INTRAVENOUS TFA-IOP RAT STUDY                                                  RAT NUMBER                                                                                8.                                                                  DOSE:     100.umoles/kg                                                        TIME:      90.minutes                                                          BODY WEIGHT:                                                                             435.grams                                                            LIVER  13.02 2.99          2.63 .20                                                                               201.73                                                                             6.04 .46                                                                               13.88                           SPLEEN  .63  .14           .10  .16                                                                               164.06                                                                             .24  .38                                                                                .55                            UPPER GI                                                                              1.27  .29           .18  .14                                                                               140.23                                                                             .41  .32                                                                                .94                            LOWER GI                                                                              1.54  .35           .27  .18                                                                               178.09                                                                             .63  .41                                                                               1.45                            KIDNEY 2.56  .59           .15  .06                                                                                57.84                                                                             .34  .13                                                                                .78                            LUNG   1.30  .30           .36  .28                                                                               277.64                                                                             .83  .64                                                                               1.91                            HEART  1.29  .30           .31  .24                                                                               242.85                                                                             .72  .56                                                                               1.66                            __________________________________________________________________________

                                      TABLE 7                                      __________________________________________________________________________     INTRAVENOUS TFA-IOP RAT STUDY                                                  RAT I.D.:       I-8       UMOLES INJECTED:                                                                              43.50 umoles                          COMPOUND:       TFA-IOP   LIVER WEIGHT:  13.02 grams                           DOSE:           100. umoles/kg                                                                           EXP. LENGTH:   90 minutes                            BODY WEIGHT:    435. grams                                                     __________________________________________________________________________     SAMPLE BILE FLOW       COMPOUND EXCRETION                                      PERIOD      ml/min PER CONC.            umoles/min PER                         (min)  ml/min                                                                              kg b.w.                                                                              kg l.w.                                                                             (umolar) umoles/min                                                                             kg b.w.                                                                             kg l.w.                           __________________________________________________________________________     10-0   .02093                                                                              .04811                                                                               1.60753                                                                              635.0   .013    .031  1.021                             0-10  .04071                                                                              .09359                                                                               3.12673                                                                             3010.0   .123    .282  9.411                            10-20  .03675                                                                              .08448                                                                               2.82258                                                                             5777.6   .212    .488 16.308                            20-30  .04050                                                                              .09310                                                                               3.11060                                                                             6436.1   .261    .599 20.020                            30-40  .02992                                                                              .06878                                                                               2.29800                                                                             7802.9   .233    .537 17.931                            40-50  .03047                                                                              .07005                                                                               2.34025                                                                             7641.1   .233    .535 17.882                            50-60  .02817                                                                              .06476                                                                               2.16359                                                                             8461.4   .238    .548 18.307                            60-70  .02721                                                                              .06255                                                                               2.08986                                                                             5372.5   .146    .336 11.228                            70-80  .02653                                                                              .06099                                                                               2.03763                                                                             5305.7   .141    .324 10.811                            80-90  .02586                                                                              .05945                                                                               1.98618                                                                             4663.1   .121    .277  9.262                            __________________________________________________________________________     SAMPLE                                                                               SAMPLE                                                                               UMOLES       PERCENTAGE OF DOSE                                    PERIOD                                                                               WEIGHT                                                                                IN   RUNNING                                                                               IN    RUNNING                                                                               PER gm.                                                                              PER kg.                            (min) (grams)                                                                              SAMPLE                                                                               TOTAL  SAMPLE                                                                               TOTAL  SAMPLE                                                                               BODY WT.                           __________________________________________________________________________     10-0  .20930                                                                                .13   .13    .31   .31    1.46  .70                                0-10 .40710                                                                               1.23  1.36   2.82   3.12   6.92  6.48                              10-20 .36750                                                                               2.12  3.48   4.88   8.00  13.28 11.22                              20-30 .40500                                                                               2.61  6.09   5.99  14.00  14.80 13.78                              30-40 .29920                                                                               2.33  8.42   5.37  19.36  17.94 12.34                              40-50 .30470                                                                               2.33  10.75  5.35  24.71  17.57 12.38                              50-60 .28170                                                                               2.38  13.13  5.48  30.19  19.45 12.60                              60-70 .27210                                                                               1.46  14.60  3.36  33.56  12.35  7.73                              70-80 .26530                                                                               1.41  16.00  3.24  36.79  12.20  7.44                              80-90 .25860                                                                               1.21  17.21  2.77  39.56  10.72  6.37                              __________________________________________________________________________

                                      TABLE 8                                      __________________________________________________________________________     INTRAVENOUS IOP RAT STUDY                                                      RAT I.D.:       I-6       UMOLES INJECTED:                                                                              42.22 umoles                          COMPOUND:       IOP       LIVER WEIGHT:  11.98 grams                           DOSE:           104. umoles/kg                                                                           EXP. LENGTH:   90 minutes                            BODY WEIGHT:    406. grams                                                     __________________________________________________________________________     SAMPLE BILE FLOW       COMPOUND EXCRETION                                      PERIOD      ml/min PER CONC.            umoles/min PER                         (min)  ml/min                                                                              kg b.w.                                                                              kg l.w.                                                                             (umolar) umoles/min                                                                             kg b.w.                                                                             kg l.w.                           __________________________________________________________________________     10-0                                                                           no sample weight -                                                             no sample conc. -                                                               0-10  .01375                                                                              .03386                                                                               1.14750                                                                             1605.8   .022    .054 1.843                             10-20  .00867                                                                              .02136                                                                               .72404                                                                              8659.4   .075    .185 6.270                             20-30  .01077                                                                              .02652                                                                               .89866                                                                              10504.9  .113    .279 9.440                             30-40  .00977                                                                              .02406                                                                               .81528                                                                              9854.3   .096    .237 8.034                             40-50  .01161                                                                              .02861                                                                               .96953                                                                              9667.6   .112    .277 9.373                             50-60  .00904                                                                              .02225                                                                               .75417                                                                              7316.4   .066    .163 5.518                             60-70  .01072                                                                              .02640                                                                               .89457                                                                              7529.1   .081    .199 6.735                             70-80  .01018                                                                              .02506                                                                               .84942                                                                              7758.8   .079    .194 6.590                             80-90  .00977                                                                              .02407                                                                               .81586                                                                              9564.6   .093    .230 7.803                             __________________________________________________________________________     SAMPLE                                                                               SAMPLE                                                                                UMOLES      PERCENTAGE OF DOSE                                    PERIOD                                                                               WEIGHT                                                                               IN    RUNNING                                                                               IN    RUNNING                                                                               PER gm.                                                                              PER kg.                            (min) (grams)                                                                              SAMPLE                                                                               TOTAL  SAMPLE                                                                               TOTAL  SAMPLE                                                                               BODY WT.                           __________________________________________________________________________     10-0                                                                           no sample concentration, thus cannot calculate these values -                   0-10 .1347 .22    .22    .52   .52    3.80 1.29                               10-20 .08674                                                                               .75    .97   1.78   2.30  20.51 4.38                               20-30 .10766                                                                               1.13  2.10   2.68   4.98  24.88 6.60                               30-40 .09767                                                                               .96   3.07   2.28   7.26  23.34 5.61                               40-50 .11615                                                                               1.12  4.19   2.66   9.92  22.90 6.55                               50-60 .09035                                                                               .66   4.85   1.57  11.48  17.33 3.86                               60-70 .10717                                                                               .81   5.66   1.91  13.40  17.83 4.71                               70-80 .10176                                                                               .79   6.45   1.87  15.27  18.38 4.61                               80-90 .09774                                                                               .93   7.38   2.21  17.48  22.65 5.45                               __________________________________________________________________________ 

What is claimed is:
 1. A modified organic contrast agent analog, comprising N-triflouroacetyl-iopanoic acid. 